The present invention relates to novel salicylamide derivatives, to a process for producing the same and to drugs containing the same as the active ingredient. More particularly, the present invention relates to novel salicylamide derivatives exerting an effect of inhibiting the activation of NF-xcexaB and useful as anti-inflammatory agents and immunosuppressive agents, to intermediates in the production thereof, to a process for producing the same, and to drugs containing the salicylamide derivatives or salts thereof as the active ingredient.
Anti-inflammatory agents conventionally used include steroid agents, prostaglandin synthesis inhibitors and so forth. Also, cyclosporin, FK506 (tacrolimus) and so forth have been used as immunosuppressive agents. However, it has been pointed out that these drugs have problems in effects and side effects.
In particular, generally many of them have strong side effects, which is a severe limit upon their use as anti-inflammatory agents and immunosuppressive agents.
Accordingly, it has been desired to discover or create novel drugs exerting little side effects and having novel chemical structures and operating mechanisms, so that there have been made studies for discovering or creating novel compounds that have different chemical structures and operating mechanisms from those of conventionally used drugs and exhibiting excellent anti-inflammatory activity or immunosuppressing activity.
NF-xcexaB was identified as a nucleoprotein bonded to the enhancer of immunoglobulin xcexa-chain gene (Cell 46, 705-716, 1986) and at first it was considered to be a transcription factor specific to B cells but afterwards it revealed that it exists in various types of cells. NF-xcexaB is a hetero dimer consisting of two subunits and is constituted by various combinations of p50 or p52 having Rel homology domain (RHD) of about 300 amino acids with RelA, c-Rel or RelB (Annu. Rev. Immunol., 14, 649-681, 1996).
NF-xcexaB is a dominant transcription factor in biophylaxis reaction and genes induced by NF-xcexaB includes besides immunoglobulin, cytokines (IL-1, IL-2, IL-6, IL-8, TNF, etc.), cell adhesion factors (E-selectin, ICAM-1, VCAM-1, etc.), nitrogen oxide (NO) synthetase, Fas ligand, etc., most of which are deeply concerned in immune response or inflammatory reaction (Cell, 87, 13-20, 1996).
Factors known to cause activation of NF-xcexaB include besides TNF-xcex1, IL-1, antigen stimulation, TPA, UV, activated oxygen (Annu. Rev. Immunol., 12, 141-179, 1994). Therefore, it is conceived that stimulation of cells with TNF-xcex1 or the like and discovery of a low molecular weight substance induced by the stimulation that inhibits activation of NF-xcexaB will undergo further development of anti-inflammatory agents and immunosuppressive agents.
In consideration of the above problems, the present inventors have repeated screening extensively and as a result they have found that novel salicylamide derivatives having specified chemical structures, i.e., compounds represented by the formula (1a) (DHM2EQ) and the compounds represented by the formula (1b) (DHM3EQ) described hereinbelow exert an effect of inhibiting the activation of NF-xcexaB, thereby achieving the present invention.
That is, the present invention provides the following novel salicylamide derivatives, a process for producing the same, and drugs containing the same as the active ingredient.
[1] Salicylamide derivatives represented by formula (1) 
wherein R1represents a hydrogen atom or a C2-4 alkanoyl group, R2 represents a group represented by the following formulae (A), (B), (C), (D), (E), (F) or (G): 
Wherein R3 represents a C1-4 alkyl group.
[2] Salicylamide derivatives as described in [1] above represented by formulae (1a) or (1b) 
[3] Salicylamide derivatives as described in [1] above, represented by formula (2) 
wherein the symbol in the formula has the same meaning as described in [1] above.
[4] Salicylamide derivatives as described in [1] above, represented by formula (3) 
wherein the symbols in the formula have the same meanings as described in [1] above.
[5] Salicylamide derivatives as described in [1] above, represented by formula (4) 
wherein the symbol in the formula has the same meaning as described in [1] above.
[6] A salicylamide derivative as described in [1] above, represented by formula (5) 
[7] Salicylamide derivatives as described in [1] above, represented by formula (6) 
wherein the symbol in the formula has the same meaning as described in [1] above.
[8] A process for producing salicylamide derivatives represented by formula (2) 
wherein the symbol in the formula has the same meaning as in described above, comprising reacting 2,5-dimethoxyaniline with O-alkanoylsalicyloyl halide represented by formula (7) 
wherein R1 has the same meaning as described in [1] above, and X represents a halogen atom.
[9] A process for producing salicylamide derivatives represented by formula (3) 
wherein the symbols in the formula have the same meanings as described above, comprising reacting a salicylamide derivative represented by formula (2) 
wherein the symbol in the formula has the same meaning as in [1] above, with an alkanol represented by formula R3OH wherein R3 is a C1-4 alkyl group, in the presence of a compound represented by a formula C6H3I(OAc)2 wherein Ac is an acetyl group.
[10] A process for producing salicylamide derivatives represented by formula (4) 
wherein the symbol in the formula has the same meaning as described above, comprising subjecting a salicylamide derivative represented by formula (3) 
wherein the symbols in the formula have the same meanings as in [1] above, to epoxidation.
[11] A process for producing a salicylamide derivative represented by formula (5) 
xe2x80x83comprising subjecting a salicylamide derivative represented by formula (4) 
wherein the symbols in the formula have the same meanings as described in [1] above, to dedialkylketalation.
[12] A process for producing salicylamide derivatives represented by formula (6) 
wherein the symbol in the formula has the same meaning as described above, comprising subjecting a salicylamide derivatives represented by formula (4) 
wherein the symbols in the formula have the same meanings as in [1] above, to reduction.
[13] A process for producing a salicylamide derivative represented by formula (1a) 
xe2x80x83comprising subjecting a salicylamide derivative represented by formula (5) 
xe2x80x83to reduction.
[14] A process for producing a salicylamide derivative represented by formula (1b) 
xe2x80x83comprising subjecting a salicylamide derivative represented by formula (6) 
wherein the symbol in the formula has the same meaning as described in [1] above, to dedialkylketalation.
[15] A drug comprising a salicylamide derivative represented by formulae (1a) or (1b) as described in [2] above or a salt thereof as the active ingredient.
[16] An agent for inhibiting the activation of NF-xcexaB comprising a salicylamide derivative represented by formulae (1a) or (1b) as described in [2] above or a salt thereof as the active ingredient.
[17] Anti-inflammatory agent or immunosuppressive agent, comprising a salicylamide derivative represented by formulae (1a) or (1b) as described in [2] above or a salt thereof as the active ingredient.